Musashi-1-A Stemness RBP for Cancer Therapy?
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ABSTRACT:
SUBMITTER: Bley N
PROVIDER: S-EPMC8148009 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Previously we reported that mithramycin represses multiple pathways critical for stem cell signaling and pluripotency in lung cancer cells. This phenomenon coincided with decreased side population fraction and dramatic dose-dependent growth arrest of lung cancer cells in vitro and in vivo. In the present study, microarray, quantitative reverse transcriptase polymerase chain reaction and immunoblot experiments were performed to further examine the effects of mithramycin on stem cell gene expression in lung cancer cells. This analysis revealed that mithramycin significantly inhibited expression of musashi-2 (MSI2), which encodes a RNA binding protein that mediates self-renewal and pluripotency in normal stem cells and has been implicated in mediating aggressive phenotype of a variety of human malignancies. MSI2 expression levels were significantly increased in non–small cell lung cancer lines and were even more dramatically elevated in small-cell lung cancer lines relative to cultured normal human respiratory epithelial cells (small airway epithelial cells / normal human bronchial epithelia / human bronchial epithelial cells; P?<?0.001). MSI2 expression levels in primary lung cancers were significantly higher than those detected in adjacent paired normal lung parenchyma (P?<?0.0003). Consistent with its putative role as a pluripotency factor, MSI2 messenger RNA as well as protein levels were significantly increased in induced pluripotent stem cells derived from normal human small airway epithelial cells, as well as side population fractions of lung cancer cells. Transient knock-down of MSI2 significantly inhibited proliferation of lung cancer cells; this phenomenon coincided with downregulation of octamer-binding transcription factor 4 (Oct4), Nanog, and MYC. To date, we have been unable to stably knock-down MSI2 in lung cancer cells in vitro or in vivo, suggesting a strong selection pressure to maintain expression of this pluripotency factor during pulmonary carcinogenesis. Under conditions potentially achievable in clinical settings, mithramycin significantly inhibited MSI2 expression in lung cancer cells in vitro and in vivo in a time- and dose-dependent manner. Collectively, these finding suggest MSI2 is a potential master regulator of stem cell gene expression and pluripotency in lung cancer cells, and a novel target for lung cancer therapy.
| S-EPMC5946505 | biostudies-literature
Project description:Mortalin/mtHsp70 is a member of Hsp70 family of proteins. Enriched in a large variety of cancers, it has been shown to contribute to the process of carcinogenesis by multiple ways including inactivation of tumor suppressor p53 protein, deregulation of apoptosis and activation of EMT signaling. In this study, we report that upregulation of mortalin contributes to cancer cell stemness. Several cancer cell stemness markers, such as ABCG2, OCT-4, CD133, ALDH1, CD9, MRP1 and connexin were upregulated in mortalin-overexpressing cells that showed higher ability to form spheroids. These cells also showed higher migration, and were less responsive to a variety of cancer chemotherapeutic drugs. Of note, knockdown of mortalin by specific shRNA sensitized these cells to all the drugs used in this study. We report that low doses of anti-mortalin molecules, MKT-077 and CAPE, also caused similar sensitization of cancer cells to chemotherapeutic drugs and hence are potential candidates for effective cancer chemotherapy.
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Project description:The biological complexity of cancer represents a tremendous clinical challenge, resulting in the frequent failure of current treatment protocols. In the rapidly evolving scenario of a growing tumor, anticancer treatments impose a drastic perturbation not only to cancer cells but also to the tumor microenvironment, killing a portion of the cells and inducing a massive stress response in the survivors. Consequently, treatments can act as a double-edged sword by inducing a temporary response while laying the ground for therapy resistance and subsequent disease progression. Cancer cell dormancy (or quiescence) is a central theme in tumor evolution, being tightly linked to the tumor's ability to survive cytotoxic challenges, metastasize, and resist immune-mediated attack. Accordingly, quiescent cancer cells (QCCs) have been detected in virtually all the stages of tumor development. In recent years, an increasing number of studies have focused on the characterization of quiescent/therapy resistant cancer cells, unveiling QCCs core transcriptional programs, metabolic plasticity, and mechanisms of immune escape. At the same time, our partial understanding of tumor quiescence reflects the difficulty to identify stable QCCs biomarkers/therapeutic targets and to control cancer dormancy in clinical settings. This review focuses on recent discoveries in the interrelated fields of dormancy, stemness, and therapy resistance, discussing experimental evidences in the frame of a nonlinear dynamics approach, and exploring the possibility that tumor quiescence may represent not only a peril but also a potential therapeutic resource.
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Project description:ObjectiveTo investigate the characteristics of the tumor immune microenvironment in patients with gastrointestinal stromal tumor (GIST) and identify cancer stem-like properties of GIST to screen potential druggable molecular targets.MethodsThe gene expression data of 60 patients with GIST was retrieved from the Array Express database. CIBERSORT was applied to calculate the level of immune infiltration. ssGSEA and ESTIMATE were used to calculate the cancer stemness index and tissue purity. The Connectivity Map (CMAP) database was implemented to screen targeted drugs based on cancer stem-like properties of GIST.ResultThere was a difference in the level of immune infiltration between the metastasis and non-metastasis GIST groups. The low level of T-cell infiltration was correlated with high tumor purity and tumor stemness index, and the correlation coefficients were -0.87 and -0.61 (p < 0.001), respectively. Furthermore, there was a positive correlation between cancer stemness index and cell purity (p < 0.001). The cancer stemness index in the metastasis group was higher than that in the non-metastasis group (p = 0.0017). After adjusting for tumor purity, there was no significant correlation between T-cell infiltration and cancer stemness index (p = 0.086). Through the pharmacological mechanism of topoisomerase inhibitors, six molecular complexes may be the targets of GIST treatment.ConclusionImmune infiltration in GIST patients is related to cancer stem-like properties, and the correlation relies on tumor purity. Cancer stemness index can be used as a new predictive biomarker of tumor metastasis and targets of drug therapy for GIST patients.
| S-EPMC8678045 | biostudies-literature
Project description:ObjectiveAs a critical feature of cancers, stemness is acknowledged as a contributor to the development of drug resistance in gastric cancer (GC). LncRNAs have been revealed to participate in this process. In this study, we tried to develop a stemness-related lncRNA pair signature as guidance for clinical decisions.MethodsThe analysis was initiated by collecting stemness-related lncRNAs in TCGA cohort. The differentially expressed stemness-related lncRNAs between normal and tumor tissues in GC patients from TCGA datasets were further collected to establish the signature based on Lasso and Cox regression analyses. The predictive efficacy of the signature for chemotherapy and immunotherapy was also tested. The practicality of this signature was also validated by Zhongshan cohort.ResultsA 13-DEsrlncRNA pair-based signature was established. The cutoff point acquired by the AIC algorithm divided the TCGA cohort into high and low risk groups. We found that the low-risk group presented with better survival (Kaplan-Meier analysis, p < 0.001). Cox regression analyse was also conducted to confirm the signature as an independent risk factor for GC {p < 0.001, HR = 1.300, 95% CI (1.231-1.373)]}. As for the practicality of this signature, the IC50 of cytotoxic chemotherapeutics was significantly higher in the high-risk group. The low-risk group also presented with higher immunophenoscore (IPS) in both the "CTLA4+ PD1+" (Mann-Whitney U test, p = 0.019) and "CTLA4- PD1+" (Mann-Whitney U test, p = 0.013) groups, indicating higher sensitivity to immunotherapy. The efficacy of the signature was also validated by Zhongshan cohort.ConclusionsThis study could not only provide a stemness-related lncRNA signature for survival prediction in GC patients but also established a model with predictive potentials for GC patients' sensitivity to chemotherapy and immunotherapy.
| S-EPMC8482617 | biostudies-literature
Project description:Excess iron causes cancer and is thought to be related to carcinogenesis and cancer progression including stemness, but the details remain unclear. Here, we hypothesized that stemness in cancer is related to iron metabolism and that regulating iron metabolism in cancer stem cells (CSCs) may be a novel therapy. In this study, we used murine induced pluripotent stem cells that expressed specific stem cell genes such as Nanog, Oct3/4, Sox2, Klf4, and c-Myc, and two human cancer cell lines with similar stem cell gene expression. Deferasirox, an orally available iron chelator, suppressed expression of stemness markers and spherogenesis of cells with high stemness status in vitro. Combination therapy had a marked antitumor effect compared with deferasirox or cisplatin alone. Iron metabolism appears important for maintenance of stemness in CSCs. An iron chelator combined with chemotherapy may be a novel approach via suppressing stemness for CSC targeted therapy.
| S-EPMC6406536 | biostudies-literature
Project description:Although antiestrogen therapies are successful in many patients with estrogen receptor alpha-positive (ER?+) breast cancer, 25% to 40% fail to respond. Although multiple mechanisms underlie evasion of these treatments, including tumor heterogeneity and drug-resistant cancer stem cells (CSC), further investigations have been limited by the paucity of preclinical ER?+ tumor models. Here, we examined a mouse model of prolactin-induced aggressive ER?+ breast cancer, which mimics the epidemiologic link between prolactin exposure and increased risk for metastatic ER?+ tumors. Like a subset of ER?+ patient cancers, the prolactin-induced adenocarcinomas contained two major tumor subpopulations that expressed markers of normal luminal and basal epithelial cells. CSC activity was distributed equally across these two tumor subpopulations. Treatment with the selective estrogen receptor downregulator (SERD), ICI 182,780 (ICI), did not slow tumor growth, but induced adaptive responses in CSC activity, increased markers of plasticity including target gene reporters of Wnt/Notch signaling and epithelial-mesenchymal transition, and increased double-positive (K8/K5) cells. In primary tumorsphere cultures, ICI stimulated CSC self-renewal and was able to overcome the dependence of self-renewal upon Wnt or Notch signaling individually, but not together. Our findings demonstrate that treatment of aggressive mixed lineage ER?+ breast cancers with a SERD does not inhibit growth, but rather evokes tumor cell plasticity and regenerative CSC activity, predicting likely negative impacts on patient tumors with these characteristics.Significance: This study suggests that treatment of a subset of ER?+ breast cancers with antiestrogen therapies may not only fail to slow growth but also promote aggressive behavior by evoking tumor cell plasticity and regenerative CSC activity. Cancer Res; 78(7); 1672-84. ©2018 AACR.
| S-EPMC5882549 | biostudies-literature
Project description:Aberrant gene expression that drives human cancer can arise from epigenetic dysregulation. Although much attention has focused on altered activity of transcription factors and chromatin-modulating proteins, proteins that act posttranscriptionally can potently affect expression of oncogenic signaling proteins. The RNA-binding proteins (RBP) Musashi-1 (MSI1) and Musashi-2 (MSI2) are emerging as regulators of multiple critical biological processes relevant to cancer initiation, progression, and drug resistance. Following identification of Musashi as a regulator of progenitor cell identity in Drosophila, the human Musashi proteins were initially linked to control of maintenance of hematopoietic stem cells, then stem cell compartments for additional cell types. More recently, the Musashi proteins were found to be overexpressed and prognostic of outcome in numerous cancer types, including colorectal, lung, and pancreatic cancers; glioblastoma; and several leukemias. MSI1 and MSI2 bind and regulate the mRNA stability and translation of proteins operating in essential oncogenic signaling pathways, including NUMB/Notch, PTEN/mTOR, TGFβ/SMAD3, MYC, cMET, and others. On the basis of these activities, MSI proteins maintain cancer stem cell populations and regulate cancer invasion, metastasis, and development of more aggressive cancer phenotypes, including drug resistance. Although RBPs are viewed as difficult therapeutic targets, initial efforts to develop MSI-specific inhibitors are promising, and RNA interference-based approaches to inhibiting these proteins have had promising outcomes in preclinical studies. In the interim, understanding the function of these translational regulators may yield insight into the relationship between mRNA expression and protein expression in tumors, guiding tumor-profiling analysis. This review provides a current overview of Musashi as a cancer driver and novel therapeutic target. Clin Cancer Res; 23(9); 2143-53. ©2017 AACR.
| S-EPMC5413399 | biostudies-literature
Project description:Carcinogenesis is a multistep process, and tumors frequently harbor multiple mutations regulating genome integrity, cell division and death. The integrity of cellular genome is closely controlled by the mechanisms of DNA damage signaling and DNA repair. The association of breast cancer susceptibility genes BRCA1 and BRCA2 with breast and ovarian cancer development was first demonstrated over 20 years ago. Since then the germline mutations within these genes were linked to genomic instability and increased risk of many other cancer types. Genomic instability is an engine of the oncogenic transformation of non-tumorigenic cells into tumor-initiating cells and further tumor evolution. In this review we discuss the biological functions of BRCA1 and BRCA2 genes and the role of BRCA mutations in tumor initiation, regulation of cancer stemness, therapy resistance and tumor progression.
| S-EPMC6548160 | biostudies-literature
Project description:In ovarian cancer, therapy resistance mechanisms complicate cancer cell eradication. Targeting Musashi RNA-binding proteins (MSI) may increase therapeutic efficacy. Database analyses were performed to identify gene expression associations between MSI proteins and key therapy resistance and cancer stem cell (CSC) genes. Then, ovarian cancer cells were subjected to siRNA-based dual knockdown of MSI-1 and MSI-2. CSC and cell cycle gene expression was investigated using quantitative polymerase chain reaction (qPCR), western blots, and flow cytometry. Metabolic activity and chemoresistance were assessed by MTT assay. Clonogenic assays were used to quantify cell survival post-irradiation. Database analyses demonstrated positive associations between MSI proteins and putative CSC markers NOTCH, MYC, and ALDH4A1 and negative associations with NOTCH inhibitor NUMB. MSI-2 expression was negatively associated with the apoptosis regulator p21. MSI-1 and MSI-2 were positively correlated, informing subsequent dual knockdown experiments. After MSI silencing, CSC genes were downregulated, while cell cycle progression was reduced. Metabolic activity was decreased in some cancer cells. Both chemo- and radioresistance were reduced after dual knockdown, suggesting therapeutic potential. Dual knockdown of MSI proteins is a promising venue to impede tumor growth and sensitize ovarian cancer cells to irradiation and chemotherapy.
| S-EPMC8584030 | biostudies-literature